This project continue research started with funding by an ongoing Program Project Grant. The central research goal of our current program project was to determine the extent to which there were common genetic determinants of different measures of neuroadaptation to ethanol. Genetic mapping techniques brought to fruition early during the course of the current grant allowed provisional identification of the map location of individual genes (Quantitative Trait Loci, or QTLs) affecting behavioral and pharmacological responses to ethanol. In particular, potential QTLs have been identified that are associated with multiple measures of ethanol tolerance and dependence. Our major theme to be carried forward into the Center from the initial program period is a focus on mapping and verification of provisional QTLs relevant for neuroadaptation to ethanol, and development of new genetic animal models (e.g., congenic strains) for studying the effects of verified QTLs. The ultimate goal of these studies is to identify the specific relevant genes and their functional roles. The second major theme is the use of genetic animal models to explore the neuropharmacological and neuroendocrine mechanisms underlying ethanol responses. The aims of Component #3 are related to both overall Center themes. They develop new congenic strains for studying genes affecting hypothermia and ataxia traits during tolerance and dependence, as well as other alcohol responses studies in other Center projects. They also continue to explore mechanisms through which neuroadaptation to ethanol's thermal and metabolic effects develops. The general goals of the proposed experiments are to: (1) subject selected potential thermoregulatory and ataxia QTLs to confirmation testing in populations of B6D2F2 mice; (2) develop congenic strains based on genotypes with extremes intolerance development to ethanol hypothermia and/or ataxia; (3) extend studies of the BXD RI strains to analyze the thermoregulatory, disruptive and energetic changes that occur during the development of thermal tolerance, using measures of behavioral thermoregulation and metabolism; (4) similarly, extend studies of the BXD RI strains to thermoregulatory and metabolic alterations that are seen during withdrawal; and (5) perform QTL analyzes of the latter two groups of responses.